PSMA-targeting amanitin conjugates

Abstract

The invention relates to a PSMA-targeting conjugate comprising (a) an amatoxin; (b) a small molecule PSMA-targeting moiety; and (c) optionally a linker linking said amatoxin and said small molecule PSMA-targeting moiety. The invention furthermore relates to a pharmaceutical composition comprising such conjugate.

The invention claimed is: 
     
       1. A conjugate comprising (a) an amatoxin, (b) a PSMA-binding moiety consisting of 2-[3-(1,3-dicarboxy-propyl)ureido]pentanedioic acid or 6-amino-2-[3-(1,3-dicarboxypropyl)ureido]-hexanoic acid, and (c) a linking moiety linking said amatoxin and said PSMA-binding moiety, the conjugate having structure VII or VIII 
       
         
           
           
               
               
           
         
       
       wherein each L is a linker, Ama is the amatoxin, B is a trifunctional linker element, EM is a half-life extension moiety, and R is selected from H, C 1-6 -alkyl, and p-bromobenzyl, and wherein the conjugate comprises a 1,2,3-triazole resulting from a reaction of an azide moiety of the trifunctional linker B and an alkyne moiety of said linker L connecting said amatoxin to said trifunctional linker B, and wherein said alkyne moiety is selected from propiolic acid, 3-butynoic acid, 4- pentynoic acid, 5-hexynoic acid, dibenzylcyclooctyne (DiBO), dibenzylazacyclooctynone (DBCO) and bicyclo[6.1.0]non-4-yne (BCN). 
     
     
       2. The conjugate of  claim 1 , wherein the half-life extension moiety comprises an Fc moiety of an antibody. 
     
     
       3. The conjugate of  claim 1  having the structure IX 
       
         
           
           
               
               
           
         
       
       wherein each L is a linker, Ama is the amatoxin, EM is the half-life extension moiety, and the PSMA-binding moiety consists of 2-[3-(1,3-dicarboxy-propyl)ureido]pentanedioic acid or 6-amino-2-[3-(1,3-dicarboxypropyl)ureido]-hexanoic acid. 
     
     
       4. The conjugate of  claim 1 , wherein said L-Ama is selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
       5. The conjugate of  claim 4 , wherein the conjugate is selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
       6. The conjugate of  claim 2 , wherein said Fc moiety consists of SEQ ID NO: 1 or SEQ ID NO: 3. 
     
     
       7. A pharmaceutical composition comprising a conjugate according to  claim 1 . 
     
     
       8. A method of treating cancer in a patient comprising administering a conjugate of  claim 1  to the patient, wherein the cancer is selected from breast cancer, pancreatic cancer, cholangiocarcinoma, colorectal cancer, lung cancer, prostate cancer, ovarian cancer, stomach cancer, kidney cancer, malignant melanoma, leukemia, and malignant lymphoma. 
     
     
       9. A pharmaceutical composition comprising a conjugate according to  claim 2 . 
     
     
       10. A pharmaceutical composition comprising a conjugate according to  claim 3 . 
     
     
       11. A pharmaceutical composition comprising a conjugate according to  claim 4 . 
     
     
       12. A pharmaceutical composition comprising a conjugate according to  claim 5 . 
     
     
       13. A pharmaceutical composition comprising a conjugate according to  claim 6 . 
     
     
       14. A method of treating cancer in a patient comprising administering a conjugate of  claim 2  to the patient, wherein the cancer is selected from breast cancer, pancreatic cancer, cholangiocarcinoma, colorectal cancer, lung cancer, prostate cancer, ovarian cancer, stomach cancer, kidney cancer, malignant melanoma, leukemia, and malignant lymphoma. 
     
     
       15. A method of treating cancer in a patient comprising administering a conjugate of  claim 3  to the patient, wherein the cancer is selected from breast cancer, pancreatic cancer, cholangiocarcinoma, colorectal cancer, lung cancer, prostate cancer, ovarian cancer, stomach cancer, kidney cancer, malignant melanoma, leukemia, and malignant lymphoma. 
     
     
       16. A method of treating cancer in a patient comprising administering a conjugate of  claim 4  to the patient, wherein the cancer is selected from breast cancer, pancreatic cancer, cholangiocarcinoma, colorectal cancer, lung cancer, prostate cancer, ovarian cancer, stomach cancer, kidney cancer, malignant melanoma, leukemia, and malignant lymphoma. 
     
     
       17. A method of treating cancer in a patient comprising administering a conjugate of  claim 5  to the patient, wherein the cancer is selected from breast cancer, pancreatic cancer, cholangiocarcinoma, colorectal cancer, lung cancer, prostate cancer, ovarian cancer, stomach cancer, kidney cancer, malignant melanoma, leukemia, and malignant lymphoma. 
     
     
       18. A method of treating cancer in a patient comprising administering a conjugate of  claim 6  to the patient, wherein the cancer is selected from breast cancer, pancreatic cancer, cholangiocarcinoma, colorectal cancer, lung cancer, prostate cancer, ovarian cancer, stomach cancer, kidney cancer, malignant melanoma, leukemia, and malignant lymphoma.